title: Identification and Functional Characterisation of CRK12:CYC9, a Novel Cyclin-Dependent Kinase (CDK)-Cyclin Complex in Trypanosoma brucei.
abstract: The protozoan parasite, Trypanosoma brucei, is spread by the tsetse fly and causes trypanosomiasis in humans and animals. Both the life cycle and cell cycle of the parasite are complex. Trypanosomes have eleven cdc2-related kinases (CRKs) and ten cyclins, an unusually large number for a single celled organism. To date, relatively little is known about the function of many of the CRKs and cyclins, and only CRK3 has previously been shown to be cyclin-dependent in vivo. Here we report the identification of a previously uncharacterised CRK:cyclin complex between CRK12 and the putative transcriptional cyclin, CYC9. CRK12:CYC9 interact to form an active protein kinase complex in procyclic and bloodstream T. brucei. Both CRK12 and CYC9 are essential for the proliferation of bloodstream trypanosomes in vitro, and we show that CRK12 is also essential for survival of T. brucei in a mouse model, providing genetic validation of CRK12:CYC9 as a novel drug target for trypanosomiasis. Further, functional characterisation of CRK12 and CYC9 using RNA interference reveals roles for these proteins in endocytosis and cytokinesis, respectively.
authors.affiliation: Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Séverine
authors.initials: S
authors.lastname: Monnerat
authors.forename: Cristina I
authors.initials: CI
authors.lastname: Almeida Costa
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Forkert
authors.forename: Corinna
authors.initials: C
authors.lastname: Benz
authors.forename: Alana
authors.initials: A
authors.lastname: Hamilton
authors.forename: Laurence
authors.initials: L
authors.lastname: Tetley
authors.forename: Richard
authors.initials: R
authors.lastname: Burchmore
authors.forename: Carlos
authors.initials: C
authors.lastname: Novo
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Mottram
authors.forename: Tansy C
authors.initials: TC
authors.lastname: Hammarton
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000235:genetics / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000235:genetics / Q000378:metabolism
chemical_list: D016213:Cyclins; D046912:Multiprotein Complexes; D050737:Proto-Oncogene Proteins c-crk; D015800:Protozoan Proteins